Recent human genetic studies show that LOXL1 (lysyl oxidase like 1) variants are strongly associated with pseudoexfoliation glaucoma. These findings are consistent with older literature suggesting that pseudoexfoliation glaucoma is associated with a defect in elastic fiber maintenance, since we have shown that LOXL1 plays a key role in elastic fiber homeostasis. The recent data connecting LOXL1 variants with pseudoexfoliation glaucoma combined with our long-standing interest in LOXL1-dependent elastic fiber homeostasis provides the basis for this exploratory study. Two inter-related specific aims are being proposed. First we will determine if perturbation of LOXL1 function/expression results in an ocular phenotype in the animal model consistent with the clinical features of pseudoexfoliation glaucoma. We will study our existing LOXL1 null mutant model and additional models generated through somatic gene transfer. Second, we aim to gain mechanistic insight into how the perturbation of LOLX1 function leads to pseudoexfoliation glaucoma. Analysis of the elastic fiber system in ocular tissues and its metabolites will be carried out, in addition to assays for glaucomatous changes. Given the complex inheritance of the pseudoexfoliation condition, it is likely that additional genetic and/or environmental factors could influence the development of the disease. Therefore the possibility that LOXL1 may interact with secondary factors to create the full clinical disease will also be explored. PUBLIC HEALTH RELEVANCE Disease mechanism underlying pseudoexfoliation glaucoma, a relatively common form of glaucoma, is not well understood. The proposed studies will attempt to establish a causal link between a defect in LOLX1 and pseudoexfoliation glaucoma using animal models. We expect the project to yield new insights into the pathogenic mechanism of this condition, and suggest possible strategies for disease screening and therapeutic intervention.